This proposal aims to investigate the role of programmed cell death (PCD) in pattern formation and cell fate specification in the developing vertebrate inner ear. It has been estimated that approximately half of human birth defects leading to profound childhood hearing loss may be congenital, but little is understood about the types and the timing of cell fate decisions made during ear formation or how they are regulated by genes known to be present in early otic epithelium. We will attempt to elucidate the functions of several cell death hot spots in developing ear. One prominent hot spot that arises in the ventromedial epithelium of the stage 19 (S19) chicken otocyst enlarges and persists through at least stage S29. We hypothesize that this hot spot may be associated with a signaling center that helps to direct morphogenesis of the membranous labyrinth. Cell death is also associated with the developing sensory organs of the ear. We will attempt to determine whether the development function of the PCD is to facilitate neurite ingrowth into the sensory epithelia. We will block PCD in the otic epithelium by application of caspase inhibitors and by overexpression of the human bc12 gene using a retroviral vector. Finally, we will study the distribution in the developing ear of receptors for bone morphogenetic proteins (BMP) as potential signal transducers for PCD. We will interfere with the function of these receptors by overexpressing a dominant negative form of one BMP receptor in an attempt to uncover the signaling pathway for PCD in the developing ear.